This invention relates generally to the field of combinatorial chemistry, and in particular, to chemical libraries which are synthesized into solid supports, such as beads. More specifically, the invention relates to the processing of such solid supports on an individual basis.
The use of combinatorial chemical libraries has become an important part of the drug discovery process. A variety of techniques have been proposed for producing such libraries. Of particular interest to the present invention is the split and recombine technique which is employed to produce large libraries of compounds which are synthesized on solid supports. This technique is described generally in co-pending U.S. patent application Ser. No. 09/091,954, filed Jun. 26, 1998 (internal docket no. PU3077), the complete disclosure of which is herein incorporated by reference. During synthesis, various encoding schemes may be utilized as described generally in H. Mario Geysen, "Isotope or Mass Encoding of Combinatorial Libraries," Chemistry & Biology, August 1996, 3:679-688 and D. S. Wagner et al., "Ratio Encoding Combinatorial Libraries with Stable Isotopes and Their Utility in Pharmaceutical Research," Combinatorial Chemistry & High Throughput Screening, 1998, 1, 143-153. The complete disclosures of these references are herein incorporated by reference.
One advantage of synthesizing the chemicals onto solid supports is that the solid supports serve as transport mechanisms to facilitate movement of the synthesized chemicals. The solid supports typically comprise spherical beads having a size on the order of about 90 .mu.m to about 250 .mu.m. One exemplary type of bead is a resin bead comprising a lightly cross-linked polystyrene or a polyethylene oxide grafted resin. To prevent the beads from sticking together, the beads are typically stored in wells containing a fluid. As described below, many circumstances exist where the beads need to be separated from each other and transferred to other locations.
For example, during the synthesis process, it is often desirable to evaluate the quality of the library being produced. To do so, a sampling of the beads from the library is removed and analyzed. Preferably, individual beads are removed from a pool of beads so that cleavage can be performed and the cleaved compounds be analyzed using mass spectrometry.
Following synthesis, the compounds on the beads are also analyzed. This may be accomplished, for example, by cleaving mixtures of compounds from a pool of beads. Each mixture is then screened. If hits are found in the mixture, the pool of beds must be arrayed as single beads and decoded.
When arraying the pool as single beads, each bead is individually removed from the well and transferred to a destination well. In order to optimize the results, there is a need to ensure that each destination well receives only a single bead and that all of the beads are removed from the pool of beads. Otherwise, more resources may be needed during the decoding process. Also, if there is uncertainty as to whether a bead was placed in a destination well, uncertainty may exist about whether valuable information was lost during the transfer.
When transferring beads between wells, there may also be a need to know the size of the bead being transferred. For example, sometimes the bead may be only a partial bead. In other cases, one or more beads may be stuck to the bead being transferred. Such occurrences can detrimentally affect the decoding process.
Previously proposed techniques for transporting solid supports include the use of a microscope and a pair of tweezers or glass capillaries which are sucked on by a person to attract a solid support. As such, these prior art manual processes are cumbersome, labor intensive, slow and prone to sampling error. Indeed, such manual methods are so inefficient and prone to sampling errors that they are practically useless with today's large combinatorial libraries.
Hence, it would be desirable to provide systems and methods which would overcome or greatly reduce the problems associated with prior art techniques for processing solid supports. In particular, it would be desirable to provide systems and methods for efficiently processing solid supports following a synthesis process, particular on an individual basis. The systems and methods should generally insure that a single bead is actually transferred each time it is intended to transfer only a single bead. The systems and methods should also check for partial beads or multiple beads. Finally, the systems and methods should be efficient to minimize the time required to process large quantities of beads.